Phenacyl ester of PGF2 α

ABSTRACT

The phenacyl ester of PGF 2  α represented by the formula ##STR1## is disclosed. The compound is useful for the same pharmacological and medical purposes as PGF 2  α, is useful in crystalline form as a convenient form for ease of handling, administering, and purifying.

This is a division of application Ser. No. 497,243 Pending, filed Aug.14, 1974.

BACKGROUND OF THE INVENTION

This invention relates to novel ester derivatives of prostaglandinF₂.spsb.α (hereinafter identified as "PGF₂.spsb.α "),15(S)-15-methyl-PGF₂.spsb.α, and 15(R)-15-methyl-PGF₂.spsb.α, includingtheir racemic compounds, and to processes for producing them.

PGF₂.spsb.α is represented by the formula: ##STR2## A systematic namefor PGF₂.spsb.α is7-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-trans-1-octenyl]-1.alpha.-cyclopentyl}-cis-5-heptenoicacid. PGF₂.spsb.α is known to be useful for a variety of pharmacologicaland medical purposes, for example, labor induction and abortion inpregnant animals, including humans, menstrual regulation in bothpregnant and non-pregnant animals, including humans, treatment ofasthma, and the inhibition of blood platelet aggregation. See Bergstromet al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. As toracemic PGF₂.spsb.α, see for example W. P. Schneider, Chem. Commun. 304(1969).

The 15-methyl-PGF₂.spsb.α analogs are represented by the formula:##STR3## wherein M' is ##STR4## following the usual convention whereinbroken line attachment of hydroxy to the side chain at carbon 15indicates the natural or "S" configuration. See for example Nugteren etal., Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964). The15-methyl-PGF₂.spsb.α analogs in their optically active and racemicforms are known. See for example U.S. Pat. Nos. 3,728,382 and 3,804,890.

Esters of the above compounds are known, wherein the hydrogen atom ofthe carboxyl group is replaced by a hydrocarbyl or substitutedhydrocarbyl group. Among these are the methyl ester of PGF₂.spsb.α (B.Samuelsson, J. Biol. Chem. 238, 3229 (1963)), the phenyl andalkyl-phenyl esters of PGF₂.spsb.α (British Spec. 1,282,661, DerwentFarmdoc No. 67438R), the α-naphthyl ester of PGF₂.spsb.α (Belgian PatentNo. 775,106, Derwent Farmdoc No. 33705T) and the methyl esters of15(S)-15-methyl-PGF₂.spsb.α and of 15(R)-methyl-PGF₂.spsb.α (U.S.Patents cited above).

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel ester derivatives ofPGF₂.spsb.α, 15(S)-15-methyl-PGF₂.spsb.α, and15(R)-15-methyl-PGF₂.spsb.α and their racemic compounds. It is a furtherpurpose to provide such esters in a free-flowing crystalline form. It isstill a further purpose to provide novel processes for preparing theseesters.

The presently described phenacyl-type esters include compoundsrepresented by the generic formula: ##STR5## wherein M is ##STR6##wherein R₁ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl; and wherein R₂ is hydrogen or benzoyl.Accordingly, in the presently described esters, the group ##STR7## isexemplified by: ##STR8##

For example, PGF₂.spsb.α, phenacyl ester, is represented by formula IIIwhen M is ##STR9## and wherein ##STR10## and is conveniently identifiedherein as the PGF₂.spsb.α ester of formula III-A. Racemic compounds aredesignated by the prefix "racemic" or "dl"; when that prefix is absent,the intent is to designate an optically active compound. For example,racemic 15-methyl-PGF₂.spsb.α, p-benzamidophenacyl ester, corresponds toformula III wherein M is ##STR11## and wherein ##STR12## including ofcourse not only the optically active isomer represented by formula IIIbut also its enantiomer.

The novel formula -III compounds and corresponding racemic compounds ofthis invention are each useful for the same purposes as described abovefor PGF₂.spsb.α and are used for those purposes in the same manner knownin the art, including oral, sublingual, buccai, rectal, intravaginal,intrauterine, or topical administration.

For many applications these novel prostaglandin esters which we haveobtained from certain specified phenacyl-type halides have advantagesover the corresponding known prostaglandin compounds. Thus, thesephenacyl-type esters are surprisingly stable compounds havingoutstanding shelf-life and thermal stability. In oral administrationthese esters have shown surprisingly greater efficacy than thecorresponding free acids or lower alkyl esters, whether because oflonger duration of biological activity or because of improvedlipophilicity and absorption is not certain. These esters offer afurther advantage in that they have low solubility in water and the bodyfluids and are therefore retained longer at the site of administration.

A particularly outstanding advantage of many of these phenacyl-typeesters is that they are obtained in free-flowing crystalline form,generally of moderately high melting point, in the range 50°-130° C.This form is especially desirable for ease of handling, administering,and purifying. These crystals are highly stable, for example showingpractically no decomposition at accelerated storage tests, in comparisonwith liquid alkyl esters or the free acids. This quality is advantageousbecause the compound does not lose its potency and does not becomecontaminated with decomposition products.

These crystalline esters also provide a means of purifying PGF₂.spsb.αand 15(S)-15-methyl-PGF₂.spsb.α, which are first converted to one ofthese esters, crystallized and recrystallized until pure, and thenrecovered as the free acid. One method of recovering the free acid is byenzymatic hydrolysis of the ester, for example with a lipase. See GermanPatent No. 2,242,792, Derwent Farmdoc No. 23047U.

A p-iodophenacyl ester of 15(S)-15-methyl-PGF₂.spsb.α was useful forX-ray crystallographic structure determination, E. W. Yankee et al., J.Am. Chem. Soc. 94, 3651 (1972). Various phenacyl esters have been usefulfor characterizing aliphatic acids because of their sharp meltingpoints, Shriner and Fuson, "Systematic Identification of OrganicCompounds", 3rd Ed., pp. 154-157 (1948).

Especially preferred of the novel compounds of this invention are thosecompounds which are in free-flowing crystalline form, for example:

phenacyl ester of PGF₂.spsb.α

p-phenylphenacyl ester of PGF₂.spsb.α

p-nitrophenacyl ester of PGF₂.spsb.α

p-benzami dophenacyl ester of PGF₂.spsb.α

p-naphthoylmethyl ester of PGF₂.spsb.α

α-benzoylphenacyl ester of PGF₂.spsb.α and

p-bromophenacyl ester of 15(S)-15-methyl-PGF₂.spsb.α.

the phenacyl-type esters of PGF₂.spsb.α, 15(S)-15-methyl-PGF₂.spsb.α,and 15(R)-15-methyl-PGF₂.spsb.α and their racemic compounds encompassedby formula III wherein ##STR13## is defined by ester groups A through Gare produced by the reactions and procedures described and exemplifiedhereinafter. For convenience, the prostaglandin or prostaglandin analogis referred to as "the PG compound". The term "phenacyl" is used in ageneric sense, including also substituted phenyl and naphthylderivatives.

Various methods are available for preparing these esters. Thus, by onemethod, the PG compound is converted to a sodium salt by methods knownin the art and reacted with an appropriate phenacyl halide in a solvent.

Preferred, however, is the method of simply mixing the PG compound witha phenacyl halide, preferably the bromide, and a tertiary amine in asolvent and letting the reaction proceed at a temperature generallybetween 20° and 70° C. The course of the reaction is readily followed bysampling the mixture and subjecting the samples to thin layerchromatography, usually being complete within 0.25-4.0 hr. Thereafterthe reaction mixture is worked up to yield the ester following methodsdescribed herein or known in the art, for example the product beingpurified by silica gel chromatography.

Examples of the phenacyl-type halides useful for this purpose are:phenacyl bromide, p-bromophenacyl bromide, p-phenylphenacyl bromide,p-nitrophenacyl bromide, p-benzamidophenacyl bromide,2-bromo-2'-acetonaphthone, and 2-bromo-1,3-diphenyl-1,3-propanedione. Inusing these reagents the usual precautions are taken to avoid theirlachrymatory effects.

Examples of suitable tertiary amines are triethylamine,diethylmethylamine, diisopropylethylamine, dimethylisobutylamine, anddimethylaniline.

Examples of suitable solvents are acetonitrile, dioxane, tetrahydrofuranand N,N-dimethylformamide.

The phenacyl halide is preferably used in equivalent amounts or inexcess to insure that all of the PG compound is converted to ester.Excess phenacyl halide is separated from the product by methodsdescribed herein or known in the art, for example by chromatography. Thetertiary amine is mainly used as a basic catalyst for the esterificationbut can also be used in larger amounts as the solvent.

Solid esters are converted to a free-flowing crystalline form oncrystallization from a variety of solvents, including ethyl acetate,tetrahydrofuran, methanol, ethanol, and acetone, by cooling orevaporating a saturated solution of the ester in the solvent or byadding a miscible nonsolvent such as diethyl ether, hexane, or water.The crystals are then collected by conventional techniques, e.g.filtration or centrifugation, washed with a small amount of solvent, anddried under reduced pressure. They may be dried in a current of warmnitrogen or argon, or by warming at about 60°-75° C., taking care not toexceed the melting point. Although the crystals are normally pure enoughfor many applications, they may be crystallized by the same generaltechniques to achieve improved purity after each recrystallization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples.

All temperatures are in degrees centigrade.

Silica gel chromatography, as used herein, is understood to includechromatography on a column packed with silica gel, elution, collectionof fractions, and combination of those fractions shown by thin layerchromatography (TLC) to contain the desired product free of startingmaterial and impurities.

"TLC", herein, refers to thin layer chromatography.

EXAMPLE 1

PGF₂.spsb.α, Phenacyl Ester (Formula III-A wherein M is ##STR14##

A mixture of PGF₂.spsb.α (0.20 g.), phenacyl bromide (0.25 g.), and 6ml. of 0.5% aqueous sodium carbonate in 15 ml. of methanol is heatedunder reflux with stirring for 1.5 hr. The mixture is partiallyconcentrated under reduced pressure and the residue is extracted withdichloromethane. The organic phase is washed with dilute aqueous sodiumbicarbonate, dried, and concentrated. The resulting residue is subjectedto silica gel chromatography, eluting with 40-100% ethyl acetate inSkellysolve B. The residue obtained by concentration of selectedfractions is crystallized from diethyl ether as the title compound,white free-flowing crystals, 0.151 g., m.p. 66°-67° C. (recrystd.),having infrared absorption bands at 3200, 1740, 1695, 1225, 1155, 1135,1060, 1020, 965, 760, 690 cm⁻¹.

Following the procedure of Example 1 but employing p-bromophenacylbromide instead of phenacyl bromide, there is obtained the correspondingp-bromophenacyl ester of PGF₂.spsb.α.

EXAMPLE 2

PGF₂.spsb.α, p-Phenylphenacyl Ester (Formula III-C wherein M is##STR15##

A mixture of PGF₂.spsb.α (1.92 g.), p-phenylphenacyl bromide (2.29 g.),and 0.97 ml. of triethylamine in 50 ml. of acetonitrile is heated at 60°C. until TLC shows conversion to the ester, about 45 min. The reactionmixture is partitioned between 100 ml. ethyl acetate and 200 ml. of 0.2N. aqueous citrate, pH 3.0. The organic phase is washed with 100 ml. ofwater, dried, and concentrated under reduced pressure. The residue issubjected to silica gel chromatography, eluting with chloroform-acetone(1:4). The residue obtained by concentration of selected fractions iscrystallized from ethyl acetate-hexane as the title compound, whitefree-flowing cyrstals, 0.248 g., m.p. 105.3°-110° C., having R_(f) 0.3(TLC on silica gel in ethyl acetate).

Example 3

PGF₂.spsb.α, p-Nitrophenacyl Ester (Formula III-D wherein M is ##STR16##

Following the procedure of Example 2 but using 4.168 g. of PGF₂.spsb.α,3.432 g. of p-nitrophenacyl bromide, and 1.87 ml. of triethylamine,heated in tetrahydrofuran at 60° for 15 min., there is obtained a cruderesidue. This residue is subjected to silica gel chromatography, elutingwith 300 ml. chloroform-ethyl acetate (1:1) followed by ethyl acetate.The residue obtained by concentration of selected fractions iscrystallized from ethyl acetate, upon addition of hexane as the titlecompound, free-flowing crystals, 4.49 g., m.p. 84.8°-86.0° C., havingR_(f) 0.4 (TLC on silica gel in ethyl-acetate-acetic acid (97.3)).

EXAMPLE 4

PGF₂.spsb.α, p-Benzamidophenacyl Ester (Formula III-E wherein M is##STR17##

Following the procedure of Example 2 but using 0.350 g. of PGF₂.spsb.α,0.720 g. of p-benzamidophenacyl bromide, and 2.0 ml. ofdiisopropylethylamine in 25 ml. acetonitrile at 35° for 30 min. there isobtained a crude residue. This residue is subjected to silica gelchromatography, eluting with 400 ml. ethyl acetate-hexane (7:3) followedwith 100 ml. ethyl acetate and finally 450 ml. tetrahydrofuran. Theresidue obtained by concentration of selected fractions is crystallizedfrom ethylacetate upon addition of hexane, as the title compound, 328mg., m.p. 132.3°-135.0° having R_(f) 0.3 (TLC on silica gel in ethylacetate-acetic acid, 97:3).

EXAMPLE 5

PGF₂.spsb.α, 2-Naphthoylmethyl Ester (Formula III-F wherein M is##STR18##

Following the procedure of Example 2 using 0.515 g. of PGF₂.spsb.α,0.424 g. of 2-bromo-2'-acetonaphthone, and 0.277 ml. ofdiisopropylethylamine in 10 ml. of acetonitrile, and crystallizing fromethyl acetate-hexane, there is obtained a crude solid product, 0.542 g.This product is subjected to silica gel chromatography, eluting withethyl acetate-acetone (4:1). The residue obtained by concentration ofselected fractions, an oil, 0.322 g., is crystallized from ethylacetate-hexane as the title compound, white free-flowing crystals, 0.287g., m.p. 79.0°-80.0° C., having R_(f) 0.6 (TLC on silica gel in ethylacetate-acetone (4:1)).

EXAMPLE 6

PGF₂.spsb.α, α-Benzoylphenacyl Ester (Formula III-G, wherein M is##STR19##

Following the procedure of Example 2 but using 0.719 g. of PGF₂.spsb.α,0.606 g. of 2-bromo-1,3-diphenyl-1,3-propanedione, and 0.348 ml. ofdiisopropylethylamine in 10 ml. acetonitrile at 70° C. for 30 min. thereis obtained a crude residue. This residue is subjected to silica gelchromatography, eluting with ethyl acetate-acetone-water (70:30:3). Theresidue obtained by concentration of selected fractions is crystallizedfrom ethyl acetate upon addition of hexane as the title compound,free-flowing crystals 322 mg., m.p. 111.3°-114.0° C., having R_(f) 0.6(TLC on silica gel in ethyl acetate-acetone (1:1)).

EXAMPLE 7

15(S)-15-Methyl-PGF₂.spsb.α, p-Bromophenacyl Ester (Formula III-B,wherein M is ##STR20##

A mixture of 15(S)-15-methyl-PGF₂.spsb.α (0.114 g.), p-bromophenacylbromide (0.171 g.), and 3 ml. of aqueous 0.5% sodium carbonate solutionin 9 ml. of methanol is stirred at about 25° C. for 90 hr., then refluxfor 1.5 hr. The mixture is concentrated under reduced pressure and theresidue is taken up in dichloromethane. The organic phase is washed withdilute aqueous sodium bicarbonate, dried and concentrated. The residueis subjected to silica gel chromatography eluting with 5-40% acetone indichloromethane. The residue obtained by concentration of selectedfractions is crystallized from diethyl ether-hexane (1:1) as the titlecompound, white free-flowing crystals, 0.04 g., m.p. 86.5°-87.5° C.

Following the procedures of Examples 1-7 but employing the racemic formsof the PG compounds, there are obtained the corresponding esters ofracemic PG compounds.

EXAMPLES 8-13

The phenacyl-type esters of 15(S)-15-methyl-PGF₂.spsb.α of Table I beloware obtained following the procedures of Example 4, wherein theprostaglandin compound is reacted in the presence ofdiisopropylethylamine with the appropriate phenacyl halide reagentlisted in the Table. The crude products, obtained by concentration underreduced pressure, are purified by means described herein or known in theart, including partitioning, solvent extraction, washing, silica gelchromatography, trituration, or crystallization.

Following the procedures of Examples 8-13 but employing the racemic formof the PG compound, there are obtained the corresponding esters of theracemic PG compound.

                  TABLE I                                                         ______________________________________                                        Esters of 15(S)-15-Methyl PGF.sub.2α                                    (Refer to formula III wherein M is                                             ##STR21##                                                                                               Product 15(S)-                                                                15-Methyl-PGF.sub.2α                         Example                                                                              Phenacyl Halide     ester of formula:                                  ______________________________________                                         8     phenacyl bromide    III-A                                               9     p-phenylphenacyl bromide                                                                          III-C                                              10     p-nitrophenacyl bromide                                                                           III-D                                              11     p-benzamidophenacyl bromide                                                                       III-E                                              12     2-bromo-2'-acetonaphthone                                                                         III-F                                              13     2-bromo-1,3-diphenyl-1,3-                                                                         III-G                                                     propanedione                                                           ______________________________________                                    

EXAMPLE 14

15(R)-15-Methyl-PGF₂.spsb.α, p-Nitrophenacyl Ester (Formula III-Dwherein M is ##STR22##

Following the procedures of Example 4, but using15(R)-15-methyl-PGF₂.spsb.α (0.182 g.), p-nitrophenacyl bromide (0.350g.), and diisopropylethylamine (0.11 ml.) in acetonitrile (5 ml.), thereis obtained a crude residue. This residue is subjected to silica gelchromatography, eluting with dichloromethane-acetonitrile-methanol(30:70:1) to yield the title compound, 0.19 g., a colorless oil havingR_(f) 0.6 (TLC) on silica gel in dichloromethane-acetonitrile (3:7)).

Likewise following the procedures of Example 4 but using15(R)-15-methyl-PGF₂.spsb.α with each of the phenacyl halide reagents ofTable II, there are obtained the corresponding phenacyl-type esters of15(R)-15-methyl-PGF₂.spsb.α of Table II.

Likewise following the procedures of Examples 15-20 but employing theracemic forms of the PG compound, there are obtained the correspondingesters of the racemic PG compound.

                  TABLE II                                                        ______________________________________                                        Esters of 15(R)-15-Methyl-PGF.sub.2α                                    (Refer to formula III wherein M is                                             ##STR23##                                                                                                Product 15(R)-                                                                15-Methyl-PGF.sub.2α                        Example                                                                              Phenacyl Halide      ester of formula:                                 ______________________________________                                        15     phenacyl bromide     III-A                                             16     p-bromophenacyl bromide                                                                            III-B                                             17     p-phenylphenacyl bromide                                                                           III-C                                             18     p-benzamidophenacyl bromide                                                                        III-E                                             19     2-bromo-2'-acetonaphthone                                                                          III-F                                             20     2-bromo-1,3-diphenyl-1,3-                                                                          III-G                                                    propanedione                                                           ______________________________________                                    

I claim:
 1. The phenacyl ester of PGF₂.spsb.α.
 2. Free-flowing crystalsof a compound of the formula: ##STR24##